The overall goal of this project is to study variation in Alu retroposons in human populations. Alu elements compose approximately 5% of the human genome, and many of them are polymorphic (present or absent) in humans. Their unique properties make them ideally suited to studies of genetic variation and evolutionary history: because each element is inserted into the genome only once, polarity and identify by descent can be determined unambiguously. To date, however, only a handful of these polymorphisms have been identified and analyzed, and their variation in human populations remains poorly understood. In this project, we will identify 125 new polymorphic Alu polymorphisms in a worldwide sample of 400 individuals. We will develop new statistical methods that fully exploit the properties of these polymorphisms. The data and themes developed in this project will fully exploit the properties of these polymorphisms. The data and methods developed in this project will permit us to test a series of hypotheses about modern human origins and ancient human population sizes. The trajectory of human population size has important implications for the distribution of alleles that contribute to susceptibility to complex diseases. For a subset of 10 Alu polymorphisms, haplotypes will be constructed using single nucleotide and microsatellite polymorphisms located within 20 kb of the Alu insert. This will permit us to estimate the time of insertion of Alu elements, compare linkages disequilibrium patterns in populations with different histories, and study the behavior of linkage disequilibrium in well-controlled settings. These project will contribute to our understanding of human genetic evolution and the ways in which it influences the genetic variability that underlies complex human diseases.